Importance of dose of type II collagen in suppression of collagen-induced arthritis by nasal tolerance

The propagation of mucosal tolerance as a therapeutic approach in autoimmune diseases remains a difficult goal to achieve, and therefore further mechanistic studies are necessary to develop potential clinical protocols to induce mucosal regulatory T cells (Tr cells). In this study we addressed whether oral or nasal proteoglycan induced functional Tr cells in the cartilage proteoglycan-induced chronic arthritis model. Both nasal and oral application of human proteoglycan before induction of disease suppressed arthritis severity and incidence. Tolerized mice showed enhanced numbers of IL-10 producing CD4+ cells in the paw-draining lymph nodes. Furthermore, CD4+ spleen cells displayed enhanced expression of molecules associated with Tr cells, such as IL-10, Foxp3, and TGF-β. Transfer of CD4+ spleen cells from mucosally tolerized donors into proteoglycan-immunized mice abolished arthritis and reduced humoral responses, indicative of Tr cells with the capacity to inhibit already induced immune responses. Tr cells were activated upon transfer, because enhanced proliferation was observed in the joint draining lymph nodes compared with activated T cells from nontolerized donors. Upon cotransfer with naive proteoglycan-specific T cells, mucosally induced Tr cells inhibited proliferation of these arthritogenic T cells in vivo. Herein we show that both oral and nasal Ag application induced Tr cells, which had a direct inhibitory effect on already established pathogenic B and T cell responses.

Section: Discussionsupporting

confidence: 92%

Oral or Nasal Antigen Induces Regulatory T Cells That Suppress Arthritis and Proliferation of Arthritogenic T Cells in Joint Draining Lymph Nodes

Broere

Wieten

Koerkamp

et al. 2008

“…1) and in fact, in some experiments, cells from mice that received this small dose of peptide were shown to be more readily stimulated by the H471 peptide than cells from control mice (data not shown). Derry et al (27) and others in our lab also recently showed that suppression of collageninduced arthritis by nasal instillation of DBA/1 mice with type II collagen was dose dependent, and the lowest dose of type II collagen (5 g) in fact aggravated disease in mice. These findings are inconsistent with previous observations made by Weiner et al (28), which suggested that low doses of Ag administered across mucosal surfaces induce active suppression of immune responses through the production of TGF-␤ by Th3 cells.…”

Section: Discussionmentioning

confidence: 61%

Histone Peptide-Induced Nasal Tolerance: Suppression of Murine Lupus

Ward

Staines

2002

Self Cite

Induced mucosal tolerance has been shown to be beneficial in preventing or treating a number of murine and human autoimmune disorders. However, this particular form of therapy has not been thoroughly tested in systemic lupus erythematosus. In this study, we investigated the conditions for induction of nasal tolerance using a histone peptide named H471 expressing a dominant T cell epitope in the histone protein H4 of mononucleosome in lupus-prone SNF1 female mice. We also tested the effect of chronic peptide nasal treatment on the development of autoimmune reactivities in these mice. Results demonstrated that a dose-dependent nasal tolerance to peptide H471 can be achieved before or after peptide sensitization in SNF1 mice. In addition, tolerance to mononucleosomes was induced by nasal instillation of SNF1 mice with H471. This was accompanied by an increase in IL-10 and suppression of IFN-γ production by lymph node cells. Suppression of Th1-type cytokines was also observed in SNF1 mice that were nasally administered with H471 before intradermal injection with the peptide. Finally, chronic nasal instillation of mice with the H471 peptide not only suppressed the development of autoantibodies, but also altered the severity of glomerulonephritis in lupus-prone SNF1 mice.

“…Recent studies of oral tolerance in an OVA-induced asthma model have examined only high-dose OVA administration (9 -12). In other disease models, the dose and the delivery route of the Ag were found to exert effects on the induction of tolerance (23)(24)(25). However, there have been few reports addressing whether feeding dose affects the induction of oral tolerance in a murine model of asthma (14).…”

Section: Discussionmentioning

confidence: 99%

Splenic Dendritic Cells Induced by Oral Antigen Administration Are Important for the Transfer of Oral Tolerance in an Experimental Model of Asthma

Nagatani

Dohi

et al. 2006

Peripheral tolerance can be induced after the feeding of Ag, which is referred to as oral tolerance. We demonstrated in this study that the oral administration of OVA induced tolerance in an experimental model of asthma in mice, and investigated which cells function as the regulatory cells in the transfer of this oral tolerance. In OVA-fed mice, the percentage of eosinophils in bronchoalveolar lavage fluid, serum IgE levels, airway hyperresponsiveness, and mRNA levels of IL-13 and eotaxin were significantly lower than found in nonfed mice. Histological examination of lung tissue showed a suppression of the accumulation of inflammatory cells in the peribronchial area of OVA-fed mice. Feeding after the first immunization or between the first and the second immunization suppressed these findings, whereas feeding just before the airway Ag challenge did not. The suppression of disease in OVA-fed mice was successfully transferred by injection of whole spleen cells of OVA-fed mice. When CD11c+ dendritic cells (DCs) were removed from splenocytes, this transfer of suppression was completely abolished. The injection of splenic DCs purified from OVA-fed mice alone transferred the suppression, whereas the injection of splenic DCs from naive mice that were cocultured with OVA in vitro did not. These data suggest that not only CD4+ T cells, but also CD11c+ DCs induced by Ag feeding are important for the active transfer of oral tolerance in this murine experimental model of asthma.